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Evidence for Deleterious Original Antigenic Sin in SARS-Cov-2

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Evidence for Deleterious Original Antigenic Sin in SARS-Cov-2 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.21.445201; this version posted May 24, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Evidence for Deleterious Original Antigenic Sin in 2 SARS-CoV-2 Immune Response 3 Sanjana R. Sen1, Emily C. Sanders2, Alicia M. Santos2, Keertna Bhuvan2, Derek Y. Tang2, 4 Aidan A. Gelston2, Brian M. Miller2, Joni L. Ricks-Oddie3,4 and Gregory A. Weiss1,2,5* 5 6 Author Affiliations: 7 1 Department of Molecular Biology & Biochemistry, University of California, Irvine, Irvine CA 92697-3900 USA 8 2 Department of Chemistry, University of California, Irvine, Irvine CA 92697-2025 USA 9 3 Center for Statistical Consulting, Department of Statistics, University of California, Irvine, Irvine CA 92697-1250 10 USA 11 4 Biostatics, Epidemiology and Research Design Unit, Institute for Clinical and Translational Sciences, University of 12 California, Irvine, Irvine CA 92697-4094 USA 13 5 Department of Pharmaceutical Sciences, University of California, Irvine, Irvine CA 92697-3958 USA 14 15 * Address correspondence to [email protected] 16 17 Corresponding Author: 18 *GAW e-mail: [email protected], Tel: +1-949-824-5566, address: 1102 Natural Sciences 2, Irvine, CA 92697-2025, 19 USA 20 21 Author Contributions: 22 S.R.S., and G.A.W. designed research; S.R.S., E.C.S., A.M.S., K.B., D.Y.T, A.A.G., and B.M.M. performed research; 23 S.R.S., E.C.S. and G.A.W. analyzed data; J.L.R. advised on statistical analysis; S.R.S. and G.A.W. wrote the 24 manuscript. 25 26 Competing Interests: 27 None. 28 29 Acknowledgements: 30 We thank Professor Elizabeth Bess and Professor Stacey Schultz-Cherry for helpful 31 conversations, Kristin Gabriel for initial bioinformatics analysis, and the patients who generously 32 donated their plasma samples (IRB# 2012-8716). We gratefully acknowledge the support of the 33 UCI COVID-19 Basic, Translational and Clinical Research Fund (CRAFT), the Allergan 34 Foundation, and UCOP Emergency COVID-19 Research Seed Funding. G.S.S and A.M.S thank 35 the Minority Access to Research Careers (MARC) Program, funded by the NIH (GM-69337). 36 J.L.R. was supported by the National Center for Research Resources and the National Center for 37 Advancing Translational Sciences from the NIH (TR001414). 38 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.21.445201; this version posted May 24, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 39 40 Abstract 41 A previous report demonstrated the strong association between the presence of 42 antibodies binding to an epitope region from SARS-CoV-2 nucleocapsid, termed Ep9, and 43 COVID-19 disease severity. Patients with anti-Ep9 antibodies (Abs) had hallmarks of original 44 antigenic sin (OAS), including early IgG upregulation and cytokine-associated injury. Thus, the 45 immunological memory of a previous infection was hypothesized to drive formation of suboptimal 46 anti-Ep9 Abs in severe COVID-19 infections. This study identifies a putative original antigen 47 capable of stimulating production of cross-reactive, anti-Ep9 Abs. From bioinformatics analysis, 48 21 potential “original” epitope regions were identified. Binding assays with patient blood samples 49 directly show cross-reactivity between Abs binding to Ep9 and only one homologous potential 50 antigen, a sequence derived from the neuraminidase protein of H3N2 Influenza A virus. This 51 cross-reactive binding affinity is highly virus strain specific and sensitive to even single amino acid 52 changes in epitope sequence. The neuraminidase protein is not present in the influenza vaccine, 53 and the anti-Ep9 Abs likely resulted from the widespread influenza infection in 2014. Therefore, 54 OAS from a previous infection could underlie some cases of COVID-19 disease severity and 55 explain the diversity observed in disease outcomes. 56 57 58 59 60 61 62 63 64 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.21.445201; this version posted May 24, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 65 Introduction 66 Original antigenic sin (OAS) occurs when the immune responses adapted for a primary 67 (or “original”) infection instead target a similar, but not identical, pathogen (Fierz & Walz, 2020). 68 Since B-cells undergo affinity maturation post-primary infection, affinity-matured Abs from 69 previous infections can sometimes outcompete naïve Abs with specificity for the new antigen 70 (Brown & Essigmann, 2021). The phenomenon has been observed for immune responses to 71 dengue fever, influenza, respiratory syncytial virus and human immunodeficiency virus (HIV) 72 (Park, Kim, Park, Lee, & Park, 2016; Welsh & Fujinami, 2007). OAS ideally accelerates pathogen 73 clearance by targeting highly conserved antigens; however, suboptimal targeting by non- 74 neutralizing Abs binding to the antigen can exacerbate disease conditions by either enhancing 75 viral infection or hyperactivating the innate immune response (Brown & Essigmann, 2021). The 76 wide range of outcomes observed in SARS-CoV-2 infected individuals, from asymptomatic to 77 fatal, has been hypothesized to result from a patient’s unique immunological memory (Fierz & 78 Walz, 2020; Kohler & Nara, 2020). 79 Reports of OAS in COVID-19 patient have largely focused on the phenomenon’s beneficial 80 or benign impacts on the immune response. For example, Abs from individuals naïve for SARS- 81 CoV-2 infection, but exposed to other common human coronaviruses (hCoV), could cross-react 82 with SARS-CoV-2 spike protein and neutralize SARS-CoV-2 pseudotypes (Ng et al., 2020). 83 Plasma collected before the pandemic had Abs cross-reactive with SARS-CoV-2 nucleocapsid 84 (NP) and spike proteins; these Abs did not confer protection against severe COVID-19 outcomes 85 (Anderson et al., 2020). Though higher rates of prior cytomegalovirus and herpes simplex virus 1 86 infections have been reported for hospitalized COVID-19 patients versus patients with milder 87 symptoms, no Ab signature linked to a molecular mechanism has been shown (Shrock et al., 88 2020). Humoral immunity to hCoVs, NL63 and 229E, has been associated with more severe 89 COVID-19 disease (Focosi et al., 2021). 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.21.445201; this version posted May 24, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 90 Recently, we reported the association of severe COVID-19 with the presence of Abs 91 binding specifically to a 21-mer peptide derived from SARS-CoV-2 NP, an epitope region termed 92 Ep9. The patients, described as αEp9(+), comprised about 27% of the sampled, SARS-CoV-2- 93 infected population (n = 186). The αEp9(+) patients (n = 34 in this report chosen for having 94 sufficient sample availability) had high, early levels of αN IgGs, typically within the first week, 95 compared to αEp9(-) patients; cytokine-related, immune hyperactivity also appeared in the 96 αEp9(+) individuals (Sen et al., 2021). These two observations suggest an OAS-based 97 mechanism for the disease severity observed in αEp9(+) patients. Here, we explore the epitope 98 homology landscape and αEp9 Ab cross-reactivity to potentially identify the original antigen 99 driving Ab-based immune response in αEp9(+) patients. 100 Results and Discussion 101 Assays measured levels of αEp9 IgGs and IgMs from αEp9(+) patients whose plasma was 102 collected at various times post-symptom onset (PSO). Consistent with the hallmarks of OAS 103 tracing a prior infection, αEp9 IgG levels appeared elevated as early as one day PSO in one 104 patient; similar IgG levels were observed in the patient population over >4 weeks (one-way 105 ANOVA, p = 0.321) (Figure 2A). Levels of αEp9 IgMs amongst patients at various times PSO 106 were also similar (one-way ANOVA, p = 0.613). The signals measured for αEp9 IgM levels were 107 significantly lower than the equivalent αEp9 IgG levels (t-test, p = 0.0181) (Figure 2B); this 108 difference could reflect lower IgM affinity, quantity, or both. 109 Searches for homologs to Ep9 in protein sequence and structural homology databases 110 suggested candidate primary antigens or potential OAS epitopes. The Basic Local Alignment 111 Sequence Tool (pBLAST) (Altschul et al., 1997) and Vector Alignment Search Tool (VAST) 112 (Madej et al., 2014) identified structurally homologous regions from betaherpesvirus 6A and 14 113 other proteins with Ep9 sequence homology spanning >7 residues. Additionally, Ep9-orthologous 114 regions from six common human coronaviruses (SARS-CoV, MERS, OC43, HKU-1, NL63, 229E) 4 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.21.445201; this version posted May 24, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 115 were also chosen for production and assays (Figure 1 A, Figure 1- supplement 1). To expedite 116 the binding measurements, the potential OAS epitope regions were subcloned into phagemids 117 encoding the sequences as fusions to the M13 bacteriophage P8 coat protein. DNA sequencing 118 and ELISA experiments demonstrated successful cloning and consistent phage display, 119 respectively. Two of the 21 epitopes failed to display on phage and were omitted from subsequent 120 investigations (Figure 1- supplement 3A). 121 The potential OAS epitopes to αEp9 Abs were tested by phage ELISA. To assess average 122 response within a patient population, pooled plasma from three sets of five αEp9(+) and five 123 αEp9(-) COVID-19 patients were coated onto ELISA plates, and tested for binding to the phage- 124 displayed potential OAS epitopes.
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